16- AND 16,16-METHYL AND ETHYL SUBSTITUTED PGF{HD 1{B -type compounds

ABSTRACT

Prostaglandin E1-type, F1-type, A1-type, and B1-type compounds with one or two methyl or ethyl substituents at the C-16 position are disclosed. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

Pike et al.

16- AND 16,16-METHYL AND ETHYL SUBSTITUTED PGF -TYPE COMPOUNDSInventors: John E. Pike, Kalamazoo; William P. Schneider, KalamazooTownship, both of Mich.

The Upjohn Company, Kalamazoo, Mich.

Filed: Feb. 11, 1974' Appl. No.: 441,519

Related U.S. Application Data Continuation-impart of Ser. No. 274,822,July 24, 1972, Pat. No. 3,813,433, which is a continuation-in-part ofSer. No. 123,388, March 11, 1971, abandoned, which is acontinuation-in-part of Ser. No. 648,992, June 26, 1967, abandoned.

Assignee:

[ Dec. 30, 1975 [51] Int. Cl. C07C 61/38; C07C 69/74 [58] Field ofSearch 260/468 D, 514 D [56] References Cited UNITED STATES PATENTS3,514,383 5/1970 Beal et al 204/158 3,796,741 3/1974 Bergstrom et al.3,812,179 5/1974 Bundy 260/514 OTHER PUBLICATIONS Corey et al., JACS 92,2586 (1970).

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Morris L. Nielsen[57] ABSTRACT Prostaglandin E -type, F -type, A -type, and B -typecompounds with one or two methyl or ethyl substituents at the C-16position are disclosed. These are useful for the same pharmacologicalpurposes as the unsubstituted prostaglandins.

10 Claims, No Drawings 16- AND 16,16-METHYL AND ETHYL SUBSTITUTED PGF-TYPE COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS This applicationis a continuation-in-part of our copending application Ser. No. 274,822,filed July 24, 1972, now US. Pat. No. 3,813,433 which is acontinuation-in-part of our then copending application Ser. No. 123,388,filed Mar. 11, 1971, now abandoned, which is a continuation-in-part ofour then copending application Ser. No. 648,992, filed June 26, 1967,now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to compositions ofmatter, and to methods and intermediates for producing them. Inparticular, the several aspects of this invention relate to novelanalogs of some of the known prostaglandins, for example, prostaglandinE (PGE prostaglandin F (PGF and PGF B prostaglandin A (PGA andprostaglandin B (PGB Each of the above-mentioned known prostaglandins isa derivative of prostanoic acid which has the following structure andatom numbering:

WE /J /I A systematic name for prostanoic acid is 7-[(2B-octyl)-cyclopent- 1 a-yl]heptanoic acid.

PGE has the following structure:

PGF has the following structure:

COOH l I I H6 H OH O coon PGB has the following structure:

The prostaglandin formulas mentioned above each have several centers ofasymmetry. Each formula represents the particular optically active formof the prostaglandin obtained from certain mammalian tissues, forexample, sheep vesicular glands, swine lung, and human seminal plasma,or by reduction of dehydration of a prostaglandin so obtained. See, forexample, Bergstrom et al., Pharmacol. Rev. 20, l (1968), and referencescited therein. The mirror image of each formula represents a molecule ofthe enantiomer of that prostaglandin. The racemic form of theprostaglandin consists of equal numbers of two types of molecules, onerepresented by one of the above formulas and the other represented bythe mirror image of that formula. Thus, both formulas are needed todefine a racemic prostaglandin. See Nature 212, 38 (1966) for discussionof the stereochemistry of the prostaglandins.

In formulas I, II, III, IV, V and VI, as well as in the formulas givenhereinafter, broken line attachments to the cyclopentane ring indicatesubstituents in alpha configuration, i.e., below the plane of thecyclopentane ring. Heavy solid line attachments to the cyclopentane ringindicate substituents in beta configuration, i.e., above the plane ofthe cyclopentane ring. The sidechain hydroxy at C-15 in Formulas II toVI is in S (a) configuration.

Each of the novel prostanoic acid analogs of this invention isencompassed by the following formula or by the combination of thatformula and its mirror image:

wherein D is one of the four carbocyclic moieties:

0 H0 0 I 0 1 a, H0 H0 wherein indicates alpha or beta attachment ofhydroxyl to the cyclopentane ring, wherein R is hydrogen, alkyl of oneto 8 carbon atoms, inclusive, or a pharmacologically acceptable cation,and wherein R and R are hydrogen, methyl, or ethyl, provided that atleast one of R and R is not hydrogen.

Formula VII, which is written in generic form for convenience,represents PGE,-type compounds when D is PFG -type compounds when D isPGF -type compounds when D is PGA -type compounds when D is and PGB-type compounds when D is In Formula VII, the configuration of thehydroxyl at C-l is alpha as in the known prostaglandins of Formulas IIto VI. Furthermore, the substituents on the C C carbon-carbon doublebond are always in trans configuration.

Each of the novel prostanoic acid analogs of this invention has one ortwo alkyl substituents at C-l6, i.e. the carbon atom adjacent to thehydroxyl-substituted C-lS carbon atoms. Thus, these novel prostanoicacid analogs may be conveniently designated l6-methylprostaglandins,l6-ethyl-prostaglandins, 16,16-dimethyl-prostaglandins,l6,16-diethyl-prostoglandins, or 16- methyl-l6-ethyl-prostaglandins,e.g. 16-methyl-PGE l-ethyl-PGF 16,16-dimethyl-PGF 16,16- diethyl-PGA16-methyl-l6-ethyl-PGB and the like.

Like the natural prostaglandins described above, these novel 16- orl6,l6-di-substituted prostaglandin analogs have several centers ofasymmetry. In addition to those found in the natural prostaglandins,there is an asymmetric center at C-16 when that carbon atom ismono-substituted as in the l6-methyl or l6-ethyl PG compounds.l6-Methyl-PGE,, therefore, has two C-l6 epimers, both having the sameconfiguration at the other asymmetric centers as that of natural PGEi.e.

alpha for the side chain at C-8 and alpha for the hydroxyls at C-ll andC-l5.

With regard to Formula VII, examples of alkyl of one to 8 carbon atoms,inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, and isomeric forms thereof.

As in the case of Formulas II to VI, Formula VII is intended torepresent optically active prostanoic acid analogs with the sameabsolute configuration as PGE. obtained from mammalian tissues. Thenovel prostanoic acid derivatives of this invention also include thecorresponding racemic compounds. Formula VII plus its mirror image arenecessary in combination to de scribe a racemic compound. Forconvenience hereinafter, when the word racemic precedes the name of oneof the novel prostanoic acid derivatives of this invention, the intentis to designate a racemic compound represented by the combination of theappropriate Formula VII and the mirror image of that formula. When theword racemic does not precede the compound name, the intent is todesignate an optically active compound represented only by theappropriate Formula VII and with the same absolute configuration as PGEobtained from animal tissues.

PGE PGF ,PGF g PGA and PGB and their esters and pharmacologicallyacceptable salts, are extremely potent in causing various biologicalresponses. For that reason, these compounds are useful forpharmacological purposes. See, for example, Bergstrom et al., Pharmacol.Rev. 20, l (1968), and references cited therein. A few of thosebiological responses are systemic arterial blood pressure lowering inthe case of the PGE, PGFp and PGA compounds as measured, for example, inanesthetized (pentobarbital sodium) pentolinium-treated rats withindwelling aortic and right heart cannulas; pressor activity, similarlymeasured, for the PFG compounds; stimulation of smooth muscle as shown,for example, by tests on strips of guinea pig ileum, rabbit duodenum, orgerbil colon; potentiation of other smooth muscle stimulants;antilipolytic activity as shown by antagonism of epinephrine-inducedmobilization of free fatty acids or inhibition of the spontaneousrelease of glycerol from isolated rat fat pads; inhibition of gastricsecretion in the case of the PGE and PGA compounds as shown in dogs withsecretion stimulated by food or histamine infusion; activity on thecentral nervous system; controlling spasm and facilitating breathing inasthmatic conditions; decrease of blood platelet adhesiveness as shownby platelet-toglass adhesiveness, and inhibition of blood plateletaggregation and thrombus formation induced by various physical stimuli,e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP,serotonin, thrombin, and collagen; and in the case of the PGE and P68compounds, stimulation of epidermal proliferation and keratinization asshown when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 pg. to

about mg. per ml. of a pharmacologically suitable liquid vehicle or asan aerosol spray, both for topical application.

The PGE, PGFa PGFp and PGA compounds are useful in the treatment ofasthma. For example, these compounds are useful as bronchodilators or asinhibitors of mediators, such as SRS-A, and histamine which are releasedfrom cells activated by an antigen-antibody complex. Thus, thesecompounds control spasm and facilitate breating in conditions such asbronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.For these purposes, these compounds are administered in a variety ofdosage forms, e.g., orally in the form of tablets, capsules, or liquids;rectally in the form of suppositories parenterally, subcutaneously, orintramuscularly, with intravenous administration being preferred inemergency situations; by'inhalation in the form of aerosols or solutionsfor nebulizers; or by insufflation in the form of powder. Doses in therange of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4times a day, the exact dose depending on the age, weight, and conditionof the patient and on the frequency and route of administration. For theabove use these prostaglandins can be combined advantageously with otheranti-asthmatic agents, such as sympathomimetics (isoproterenol,phenylephrine, ephedrine, etc); xanthine derivatives (theophylline andamionophyllin); and corticosteroids (ACTH and predinisolone). Regardinguse of these compounds see South African Pat. No. 681,055.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastic secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 g. to about 500 pg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about mg. per kg. of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

The PGE, PGF and PGFp compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situation, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF and PGFB compounds are especially useful as additives toblood, blood products, blood substituents, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animals, to the perfused body portion, attached or detached,to the recipient, or to two or all of those at a total steady state doseof about 0.001 to 10 mg. per liter of circulating fluid. It isespecially useful to use these compounds in laboratory animals, e.g.,cats, dogs, rabbits, monkeys, and rats, for these purposes in order todevelop new methods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE for example, is useful in place of or in combination withless then usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterime bleeding after abortion of delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 pg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE, PGA, and PGF compounds are useful as hypotensive agents toreduce blood pressure in mammals, including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 to about 50 pg. per kg. of body weight per minute, or in single ormultiple doses of about 25 to 500 pg. per kg. of body weight total perday.

The PGE, PGF and PGF compounds are useful in place of oxytocin to inducelabor in pregnant female animals, including man, cows, sheep, and pigs,at or near term, or in pregnant animals with intrauterine death of thefetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose of 0.01 to 50 pg per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks post-mature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started. An alternative route of administration isoral.

The PGE, PGFa and PGFp compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose, PGE or PGF for example, is administered systemically at adose level in the range 0.01 mg. to about 20 mg. per kg. of body weightof the female mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses orjust prior to menses. Intravaginal and intrauterine andalternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimparied renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. In cases of excess or inappropriateADH (antidiuretic hormone; vasopressin) secretion, the diuretic effectof these compounds is even greater. In anephretic states, thevasopressin action of these compounds is especially useful.lllustratively, the PGA compounds are useful to alleviate and correctcases of edema resulting, for example, from massive surface burns, andin the management of shock. For these purposes, the PGA compounds arepreferably first administered by intravenous injection at a dose in therange to 1000 pg. per kg. of body weight or by intravenous infusion at adose in the range 0.1 to g. per kg. of body weight per minute until thedesired effect is obtained. Subsequent doses are given by intravenous,intramuscular, or subcutaneous injection or infusion in the range 0.05to 2 mg. per kg. of body weight per day.

The PGE and PGB compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, especially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 pg/ml. of the PGB compound or several times that concentration ofthe PGE compound. Especially for topical use, these prostaglandins areuseful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The novel Formula-VII l6-alky1- and 16,16-dialkyl- PGE -PGF -PGF -PGAand -PGB compounds each cause the biological responses described abovefor the PGE, PGF PGFB PGA, and PGE compounds, respectively, and each ofthese novel compounds is accordingly useful for the abovedescribedcorresponding purposes, and is used for those purposes in the samemanner as described above.

The known PGE, PGF PGFp PGA, and PGB compounds uniformly cause multiplebiological responses even at low doses. For example, PGE causesvasodepression and smooth muscle stimulation at the same time it exertsantilipolytic activity. Moreover, for many applications, these knownprostaglandins have an inconveniently short duration of biologicalactivity. In striking contrast, the novel prostaglandin analogs ofFormula VII are substantially more specific with regard to potency incausing prostaglandin-like biological responses, and have asubstantially longer duration of biological activity. Therefore, each ofthese novel prostaglandin analogs is useful in place of one of thecorresponding above-mentioned known prostaglandins for at least one ofthe pharmacological purposes indicated above for the latter, and issurprisingly and unexpectedly more useful for that purpose because ithas a different and narrower spectrum of biological activity than theknown prostaglandin, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than the knownprostaglandin. Moreover, because of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively orally, sublingually, intravaginally, bucally,or rectally, in addition to usual intravenous, intramuscular, orsubcutaneous injection or infusion methods indicated above for the usesof the known prostaglandins. These qualities are advantageous becausethey facilitate maintaining uniform levels of these compounds in thebody with fewer, shorter, or smaller doses, and make possibleself-administration by the patient.

The l6-alkyl and 16,16-dialkyl PGE PGF, PGF PGA and PGE type compoundsencompassed by Formulas VIl are used for the purposes described above inthe free acid form, in ester form, or in pharmacologically acceptablesalt form. When the ester form is used, the ester is any of those withinthe above definition of R However, it is preferred that the ester bealkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimental animal system.

Pharmacologically acceptable salts of these Formula- VII compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron, are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 atoms, aswell as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine,piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,Z-methylpyrrolidine, l,4-dimethylpiperazine, Z-methyliperidine, and thelike, as well as amines containing water solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino- 1 butanol,2-amino-2-ethyl-l,3-propanediol, 2-amine-2- methyl- 1 -propanol,tris(hydroxymethyl )aminomethane, N-phenylethanolamine,N-(p-tertamylphenyl)- diethanolamine, galactamine, N-methyl-glucamine,N-methylglycosamine, ephedrine, phenylephrine, epinephrine, porcaine,and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of Formula VII are administered invarious ways for various purposes; e.g., intravenously, intramuscularly,subcutaneously, orally, intravaginally, rectally, buccally,sublingually, topically, and in the form of sterile implants forprolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility that R in the Formula-VII compound behydrogen or a pharmacologically acceptable cation. For subcutaneous orintramuscular injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or non-aqueous media are used. Tablets,capsules, and liquids preparations such as syrups, elixirs and simplesolutions, with the usual pharmaceutical carriers are used for oralsublingual administration. For rectal or vaginal admin- 10 istration,suppositories prepared as known in the art are used. For tissueimplants, a sterile tablet or silicone rubber capsule or other objectcontaining or impregnated with the substance is used.

The 16-alkyl and 16,16-dialkyl PGE PGF a PGF PGA and PGB, type compoundsencompassed by Formula VII are produced by the reactions and proceduresdescribed and exemplified hereinafter.

The various PGF -type and PGE, -type compounds encompassed by FormulaVII are prepared by carbonyl reduction of the corresponding PGE typecompounds. For example, carbonyl reduction of 16- methyl-PGE, gives amixture of l6-methyl-PGF and 16-methyl-PGF p These ring carbonylreductions are carried out by methods known in the art for ring carbonylreductions of known prostanoic acid derivatives. See, for example,Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969(1962), and British Specification No. 1,097,533. Any reducing agent isused which does not react with carbon-carbon double bonds or estergroups. Preferred reagents are lithium (tri-tertbutoxy)aluminum hydride,the metal borohydrides, especially sodium, potassium and zincborohydrides, and the metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride. The mixtures of alpha and beta hydroxy reductionproducts are separated into the individual alpha and beta isomers bymethods known in the art for the separation of analogous pairs of knownisomeric prostanoic acid derivatives. See, for example, Bergstrom etal., cited above, Granstrom et al., J. Biol Chem. 240, 457 (1965), andGreen et al., J. Lipid Research 5, 117 (1964). Especially preferred asseparation methods are partition chromatographic procedures, both normaland reversed phase, preparative thin layer chromatography, andcountercurrent distribution procedures.

The various PGA -type compounds encompassed by Formula VII are preparedby acidic dehydration of the corresponding PGE type compounds. Forexample, acidic dehydration of 16-ethyl-PGE gives l6-ethyl- PGA Theseacidic dehydrations are carried out by methods known in the art foracidic dehydrations of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium 11, Stockholm (1966),Interscience Publishers, New York, pp. 162-163 (1967); and BritishSpecification 1,097,533. Alkanoic acids of 2 to 6 carbon atoms,inclusive, especially acetic acid, are preferred acids for this acidicdehydration. Dilute aqueous solutions of mineral acids, e.g.,hydrochloric acid, especially in the presence of a solubilizing diluent,e.g., tetrahydrofuran, are also useful as reagents for this acidicdehydration, although these reagents may cause partial hydrolysis of anester reactant.

The various 16-alkyl and 16,16-dialkyl PGB -type compounds encompassedby Formula VII are prepared by basic dehydration of the correspondingPGE type compounds, or by contacting the corresponding PGA typecompounds with base. For example, both 16,16- dimethyl-PGE, andl6,l6-dimethyl-PGB give 16,16- dimethyl-PGB on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand sufficient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 mg. for the PCB type compound.

The various transformations of PGE -type compounds of Formula VII to thecorresponding PGF PGF p and I GB type compounds are shown in Chart A,wherein E represents /H R; i( 2)a a and wherein R R R and are as definedabove.

The novel l6-alkyl and 16,16-dialkyl PGE -type acids and esters ofFormula VII are prepared by the sequence of transformations shown inChart B wherein Formulas VIII, IX, X, XI, and XII include opticallyactive compounds as shown and racemic compounds of those formulas andthe mirror image thereof. Also in Chart B, G is (CI-I CH R and R arehydrogen, methyl, or ethyl, provided that at least one of R and R is nothydrogen; R is alkyl of one to 8 carbon atoms, inclusive; R is alkyl ofone to 5 carbon atoms, inclusive; and indicates attachment to thecyclopropane ring in exo or endo configuration. In Chart B the novel PGE-type esters of this invention are encompassed by Formula XII.

CHART A I E HO carbonyl reduction 0 (CH -C00R ,(CH -C00R acid a E E HObase base (CH -COOR The Formula-VIII bicyclo-ketone reactant of Chart Bexists in four isomeric forms, exo and endo with respect to theattachment of the moiety, and cis and trans with respect to the doublebond in that same moiety. Each of those isomers separately or variousmixtures thereof are used as reactants according to this invention toproduce substantially the same final PGE or PGA type product mixture.

The process for preparing either the exo or endo configuration of theFormula-VIII bicyclo-ketone is known to the art. See Belgian Pat. No.702,477; reprinted in Farmdoc Complete Specifications, Book 714, No.30,905, page 313, Mar. 12, 1968. See West Germany OffenlegungsschriftNo. 1,937,912; reprinted in Farmdoc Complete Specifications, Book No.14, No. 6869 R, Week R Mar. 18, 1970.

In said Belgian Pat. No. 702,477, a reaction sequence capable of formingexo ketone VIII is as follows: The hydroxy of 3-cyclopentenol isprotected, for example, with a tetrahydropyranyl group. Then adiazoacetic acid ester is added to the double bond to give an exoendomixture of a bicyclo [3.1.0] hexane substituted at 3 with the protectedhydroxy and at 6 with an esterified carboxyl. The exo-endo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester group at 6 is transformedto an aldehyde group. Then, said aldehyde group is transformed by theWittig reaction, in this case to a moiety of the formula which is in exoconfiguration relative to the bicyclo ring structure. Next, theprotective group is removed to regenerate the 3-hydroxy which is thenoxidized, for example, by the Jones reagent, i.e., chromic acid (see J.Chem. Soc. 39 (1946)), to give said exo ketone VIII.

Separation of the cis-exo and trans-exo isomers of VIII is described insaid Belgian Pat. No. 702,477. However, as mentioned above, thatseparation is usually not necessary since the cis-trans mixture isuseful as a reactant in the next process step.

COOCHs Compound XV is prepared by reactingendo-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid methyl ester withdiborane in a mixture of tetrahydrofuran and diethyl ether, a reactiongenerally known in the art, to giveendo-bicyclo[3.1.0]hexane-3-ol-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl to give the desired compound. This is then used as described insaid Offenlegungsschrift No. 1,937,912 to produce the endo form ofbicyclo-ketone VIII.

As for exo VIII, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans VIII, but this separation is usuallynot necessary since, as mentioned above, the cis-trans mixture is usefulas a reactant in the next process step.

In the processes of said Belgian patent and said Offenlegungsschrift,certain organic halides, e.g., chlorides and bromides, are necessary toprepare the Wittig reagents used to generate the generic moiety CH=CHC(R)(R )G of bicyclo-ketone VIII. These organic chlorides and bromides,GC(R )(R )CH- Cl and GC(R )(R )-CH -Br, are known in the art or can beprepared by methods known in the art. Those halides not available areprepared by reacting the corresponding primary alcohol GC(R )R )CH- 0Hwith PCI PBr or any of the other halogenating agents useful for thispurpose. Accordingly, there is used 1-bromo-2-methylhexane,l-bromo-2,2-dimethylhexane, 3-(bromomethyl)heptane, 3-(bromomethyl)-3-ethylheptane, and 3-(bromomethyl)-3-methylheptane, or thecorresponding chloro compounds, when the desired end-product is,respectively, l6-methyl- PGE,, l6,16-dimethyl-PGE,, l6-ethyl-PGE 16,16-diethyI-PGE and l6-ethyl-l6-methyl-PGE Referring to Chart B, bicycloolefin VIII is transformed to the Formula-IX compound by alkylating withan alkylation agent of the formula Hal(CH COOR wherein R is as definedabove and Hal is chloro, bromo, or iodo. Any of the alkylationprocedures known in the art to be useful for alkylating cyclic ketoneswith alkyl halides and haloalkanoic esters are used for thetransformations of VIII to IX. See, for example, the above-mentionedBelgian Pat. No. 702,477 for procedures useful here and used there tocarry out similar alkylations.

For these alkylations, it is preferred that Hal be bromo or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides, and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretetrahydrofuran and 1,2-dimethoxyethane. Otherwise, procedures forproducing and isolating the desired Formula-IX compound are within theskill of the art.

These alkylation procedures produce mixtures of alpha and betaalkylation products, i.e., a mixture of Formula-1X products wherein parthas the -(CH ),,COOR moiety attached in alpha configuration, and whereinpart has that moiety attached in beta configuration.

When about one equivalent of base per equivalent of Formula-VIII ketoneis used, the alpha configuration usually predominates. These alpha-betaisomer mixtures are separated at this stage or at any subsequent stagein the multi-step processes shown in Chart B. Silica gel chromatographyis preferred for this separatron.

The transformation of the Formula-IX olefin compound to glycol X iscarried out by reacting olefin IX with a hydroxylation reagent.Hydroxylation reagents and procedures for this purpose are known in theart. See, for example, Gunstone, Advances in Organic Chemistry, Vol. 1,pp. 103-147, Interscience Publishers, New York, N.Y. (1960). Variousisomeric glycols are obtained depending on such factors as whetherolefin IX is cis or trans and endo or exo, and whether a cis or a transhydroxylation reagent is used. Thus endocis olefin IX gives a mixture oftwo isomeric erythro glycols of Formula X with a cis hydroxylationagent, e.g., osmium tetroxide. Similarly, the endo-trans olefin IX givesa similar mixture of the same two erythro glycols with a transhydroxylation agent, e.g., hydrogen peroxide. The endo-cis olefins andthe endo-trans olefins IX give similar mixtures of two threo glycolisomers with cis and trans hydroxylation reagents, respectively. Thesevarious glycol mixtures are separated into individual isomers by silicagel chromatography. However, this separation is usually not necessary,since each isomeric erythro glycol and each isomeric threo glycol isuseful as an intermediate according to this invention and the processesoutlined in Chart B to produce final products of formulas XI, and then,according to Chart B to produce the other final products of thisinvention. Thus, the various isomeric glycol mixtures encompassed byFormula X produced from the various isomeric olefins encompassed byFormula IX are all useful for these same purposes.

Referring again to Chart B, the bis-alkanesulfonic acid ester XI isprepared by reacting glycol IX with an alkanesulfonyl chloride orbromide, or with an alkanesulfonic acid anhydride, the alkyl in eachcontaining one to 5 carbon atoms, inclusive. Alkanesulfonyl chloridesare preferred for this reaction. The reaction is carried out in thepresence of a base to neutralize the byproduct acid. Especially suitablebases are tertiary amines, e.g., dimethylaniline or pyridine. It isusually sufficient merely to mix the two reactants and the base, andmaintain the mixture in the range to 25 C. for several hours. TheFormula-XI bis-sulfonic acid ester is then isolated by procedures knownin the art.

The transformation of bis-sulfonic acid ester XI to the PGE-typecompound XII is carried out by reacting bis-ester XI with water in therange about 0 to about 60 C., preferably at 25 C., the reaction thenproceeding to completion in about to hours. It is advantageous to have ahomogenous reaction mixture. This is accomplished by adding sufficientof a water-soluble organic diluent which does not enter into thereaction. Acetone is a suitable diluent. The desired product is isolatedby evaporation of excess water and diluent if one is used. The residuecontains a mixture of Formula XII isomers which differ in theconfiguration of the side chain hydroxy, that being either a or B. Theseare separated from by-products and from each other by silica gelchromatography. A usual byproduct is the monosulfonic acid ester ofFormula XIV (Chart B). This mono-sulfonic acid ester is esterified tothe Formula-XI bis-sulfonic acid ester in the same manner describedabove for the transformation of glycol X to bis-ester XI and thus arerecycled back to additional Formula-XII final product.

The transformations of XI (Chart B) to the PGA-type compound XIII iscarried out by heating bis-ester XI in the range 40 to C. with acombination .of water, a base characterized by its Water solution havinga pH 8 to 12, and sufficient inert water-soluble organic diluent to forma basic and substantially homogenous reaction mixture. A reaction timeof one to 10 hours is usually used. Preferred bases are thewater-soluble salts of carbonic acid, especially alkali metalbicarbonates, e.g., sodium bicarbonate. A suitable diluent is acetone.The products are isolated and separated as described above for thetransformation of bis-ester XI to PGE- type product XII. The samemono-sulfonic acid ester XIV observed as a byproduct in thosetransformations is also observed during preparation of PGA-type productXIII.

For the transformations of bis-sulfonic acid ester XI to final productsXII and XIII, it is preferred to use the bis-mesyl esters, i.e.,compound XI wherein R is methyl.

The Formula-XII PGE-type compounds and the Formula-XIII PGA-typecompounds shown in Chart B are all R carboxylic acid esters, wherein Ris as defined above. Moreover, when those POE-type and PGA-type R estersare used to prepare the other prostaglandinlike compounds according toChart A, corresponding R esters are likely to be produced, especially inthe case of the PGF-type compounds. For some of the uses describedabove, it is preferred that the novel Formula- VII prostaglandin-likecompounds of this invention be in free acid form, or in salt form whichrequires the free acid as a starting material. The PGF-type esters andthe PGB-type compounds are easily hydrolyzed or saponified to the freeacids by the usual known procedures, especially when R (R is alkyl ofone to 4 carbons, inclusive, preferably methyl or ethyl.

On the other hand, the PGE-type and PGA-type esters are difficult tohydrolyze or saponify without causing unwanted structural changes in thedesired acids. There are two other procedures to make the free acidforms of these compounds.

One of those procedures is applicable mainly in preparing the free acidsfrom the corresponding alkyl esters wherein the alkyl group contains 1to 8 carbon atoms, inclusive. That procedure comprises subjecting thePG-type alkyl ester to the acylase enzyme system of a microorganismspecies of Subphylum 2 of Phylum Ill, and thereafter isolating the acid.See West Germany Offenlegungsschrift No. 1,937,678; reprinted inFarmodoc Complete Specifications, Book No. 13, No. 6863 R, Week R5, Mar.18, 1970.

Another procedure for making the free acids of the PGE-type and PGA-typeFormula-VIII compounds involves treatment of certain haloethyl esters ofthose acids with zinc metal and an alkanoic acid of 2 to 6 carbon atoms,preferably acetic acid. Those haloethyl esters are the esters wherein Ris ethyl substituted in the B-position with 3 chloro, 2 or 3 bromo, orone, 2, or

3 iodo. Of those haloethyl moieties, [3,B,/3-trichloro-- ethyl ispreferred. Zinc dust is preferred as the physical form of the zinc.Mixing the haloethyl ester with the zinc dust at about 25 C. for severalhours usually causes substantially complete replacement of the haloethylmoiety of the Formula-VII PGE- or PGA-type ester with hydrogen. The freeacid is then isolated from the reaction mixture by procedures known tothe art. This procedure is also applicable to the production ofFormula-VII PGF-type and PGB-type free acids.

Formula-IX olefins wherein R is haloethyl as above defined are necessaryas intermediates for this route to the final PGE, PGF, PGA, and PGB typefree acids. These haloethyl ester intermediates can be prepared byalkylation of olefin VIII (Chart B) with the appropriate alkylatingagent of the formula I-lal(CH COOR wherein R is haloethyl as abovedefined. However, preferred routes to the Formula-IX haloethyl esterintermediates are shown in Chart C.

In Chart C, G, R R and are as defined above. Haloethyl represents ethylsubstituted in the B-position QLA LQ ,(cHE )e-COOR R2 I Momma-G XV xv|,(CH -C00ha Ioethyl R2 I McHwuc-e I Ra XVI I I XV|| I/ICH2Ie'coo-haloethyl CH=CHC-G I Rs XX XIX with 3 chloro, 2 or 3 bromo, or 1,2, or 3 iodo, preferably -CI-I CCl R represents alkyl of one to 4 carbonatoms, inclusive, preferably methyl or ethyl.

Compound XV in Chart C is within the scope of compound IX in Chart B.Ketone XV is reduced to the corresponding hydroxy compound XVI with acarbonyl reducing agent, e.g., sodium borohydride, as described above indiscussion of Chart A. Then, hydroxy ester XVI is saponified by knownprocedures to hydroxy acid XVII. This hydroxy acid is transformed toketo haloethyl ester XX by Oxidation of the hydroxy group to keto andesterification of the carboxyl group to COOhaloethyl. As shown in ChartC, these two reactions are carried out in either order.

II aIB- e 2 CH=CHC-G CH=CHC-G However, it is preferred to oxidize firstand then esterify.

Hydroxy acid XVII is oxidized to keto acid XIX and hydroxy haloesterXVIII are oxidized to keto haloester XX by reaction with an oxidizingagent which does not attack other parts of these molecules, especiallythe ethylenic linkage of compounds XVII and XVIII. An especially usefulreagent for this purpose is the Jones reagent, i.e., acidic chromicacid. Acetone is a suitable diluent for this purpose, and a slightexcess of oxidant and temperatures at least as low as about C.,preferably about IO to about 20 C. should be used. The oxidationproceeds rapidly and is usually complete in about to about 30 minutes.Excess oxidant is destroyed, for example, by addition of a loweralkanol, advantageously isopropyl alcohol, and the aldehyde is isolatedby conventional methods, for example, by extraction with a suitablesolvent, e.g., diethyl ether. Other oxidizing agents can also be used.Examples are mixtures of chromium trioxide and pyridine or mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, J.Am. Chem. Soc. 87, 5661 I965 I-Ialoethyl esters XVIII and XX areprepared by reacting acids XVII and XIX, respectively, with theappropriate haloethanol, e.g., B,B,,8-trichloroethanol, in the presenceof a carbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g.,pyridine, preferably in the presence of an inert liquid diluent, e.g.,dichloromethane, for several hours at about 25 C.

As discussed above, the processes of Charts A and B, also utilizing theintermediates of Chart C, lead either to acids (R is hydrogen) or toalkyl esters (R or R is alkyl of one of 8 carbon atoms, inclusive). Whena Formula-VII PGE or PGF -type acid has been prepared and an alkyl esteris desired, esterification is advantageously accomplished by interactionof the acid with the appropriate diazohydrocarbon. For example, whendiazomethane is used, the methyl esters are produced. Similar use ofdiazoethane, dizaobutane, and I-diazo-Z-ethylhexane, for example, givesthe ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or-adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by meth odsknown in the art. See, for example, Organic Reactions, John Wiley &Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of thePGF-type or PGE-type compounds comprises transformation of the free acidto the corresponding silver salts, followed by interaction of the saltwith an alkyl iodide. Examples of suitable iodides are methyl iodide,ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide, and thelike. The silver salts are prepared by conventional methods, forexample, by dissolving the acid in cold dilute aqueous ammonia,evaporating the excess ammonia at reduced pressure, and then adding thestoichiometric amount of silver nitrate.

The final Formula-VII compounds prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice orprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the Formula-VII acid in water containingthe stoichiometric amount of a hydroxide, carbonate, or bicarbonatecorresponding to the inorganic salt desired. For example, such use ofsodium hydroxide, sodium carbonate, or sodium bicarbonate gives asolution of the sodium salt. Evaporation of the water or addition of awater-miscible solvent of moderate polarity, for example, a loweralkanol or a lower alkanone, gives the solid inorganic salt if that formis desired.

To produce an amine salt, the Formula-VII acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe Formula-VII acid with the stoichiometric amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

When the optically active final compound is desired, it is made byresolution of the racemic compound or by resolution of one of theasymmetric racemic intermediates. These resolutions are carried out byprocedures known in the art. For example, when final compound VII is afree acid, the d] form thereof is resolved into the d and 1 forms byreacting said free acid by known general procedures with an opticallyactive base, e.g., brucine or strychnine, to give a mixture of twodiastereoisomers which are separated by known general procedures, e.g.,fractional crystallization, to give the separate diastereoisomericsalts. The optically active acid of formula VII is then obtained bytreatment of the sale with an acid by known general procedures. Alterna-23 tively, the free acid form of olefin IX or glycol X is resolved intoseparated and 1 forms and then esterified and transformed further to thecorresponding optically active form of the final product VII asdescribed above.

Alternatively, glycol reactants X, in exo or endo form, are transformedto ketals with an optically active 1,2-g1yco1, e.g.,D-()-2,3-butanediol, by reaction of said 1,2-g1ycol with the Formula-Xcompound in the presence of a strong acid, e.g., p-toluenesulfonic acid.The resulting ketal is a mixture of a diastereoisomers which isseparated into the d and 1 diastereoisomers, each of which is thenhydrolyzed with an acid, e.g., oxalic acid, to the original ketocompound, now in optically active form. These reactions involvingoptically active glycols and ketals for resolution purposes aregenerally known in the art. See, for example, Chem. 1nd. 1664 (1961) andJ. Am. Chem. Soc. 84, 2938 (1962). Dithiols may be used instead ofglyeols.

The optically active and racemic forms of 16-methyl- PGE and -PGE,-,,,16, 16-dimethyl-PGE and -PGF 16-ethyl-PGE -ethyl-PGE and 1 and -PGF a16,16-diethyl-PGE and -PGF and 16-ethyl-16 methyl-PGE and -PGF are alsoprepared by the processes set forth and described in our copendingapplication Ser. No. 648,991, filed June 26, 1967, now issued as U.S.Pat. No. 3,514,383. Those processes use as initial reactants, all-cis16-methyl-8,11,14-eicosatrienoic acid to produce the 16-methy1prostaglandin analogs, and all cis 16,16-dimethyl-8,11,14-eicosatrienoicacid to produce the 16,16-dimethyl prostaglandin analogs. Thepreparation of all cis -methyl- 8,1 1,l4-eicosatrienoic acid is setforth and described in said issued patent. Use of 2-methylhexanone inplace of the 2-heptanone used as initial reactant in that process leadsto all-cis 16-methyl-8,l1,14-eicosatrienoic acid. Likewise,2,2-dimethylhexanone leads to 16,16- dimethyl-8,1 1,14-eicosatrienoicacid; 2-ethylhexanone leads to 16-ethyl-8,11,14-eicosatrienoic acid;2,2-diethylhexanone leads to 16,16-diethyl-8,l1,14-eicosatrienoic acid;and 2-ethyl-2-methylhexanone leads to 16-ethyl-16-methyl-8,l1,14-eicosatrienoic acid.

As set forth and described in said issued patent, allcis16-methyl-8,11,14-eicosatrienoic acid and all-cis16,l6-dimethyl-8,l1,14-eicosatrienoic acid are each transformed toracemic l6-methyl-PGE or racemic l6-methyl-PGF and to racemic16,16-dimethyl- PGE or racemic 16,16-dimethyl-PGF respectively, byreacting said acids with singlet oxygen and then treating the resultingproduct with a reducing agent to produce PGF -type derivatives or with amild reducing agent and then with a base, a metal ion catalyst, or withultraviolet light to produce the PGE- type derivatives.

Likewise, following the procedures of said issued patent, all-cis16-ethyl-8,11,14-eicosatrienoic acid is transformed to racemic16-ethyl-PGE or racemic 16- ethyl-PGF all-cis16,16-diethyl-8,l1,14-eicosatrienoic acid is transformed to racemic16,16-diethyl- PGE or racemic 16,16-diethyl-PGF and all-cis16-ethyl-l6-methyl-8,l1,14-eicosatrienoic acid is transformed to racemic16-ethyl-16-methyl-PGE or racemic l 6-ethyl-l6-methyl-PGF The opticallyactive prostaglandin analogs, l6-methyl-PGE 16-methyl-PGF16,16-dimethyl-PGE and 16,16-dimethyl-PGF are prepared as set forth anddescribed in said issued patent by resolution of the correspondingracemic forms prepared as described above. Likewise, following theprocedures of said issued patent, the optically active analogs,l6-ethyl- PGF 16-ethy1-PGF 16,16-diethyl-PGE 16,16- diethyl-PGF16-ethyl-16-methyl-PGE and 16- ethyl-16-methyl-PGF are prepared byresolution of the racemic forms. Alternatively, as set forth anddescribed in said issued patent, optically active 16methyl and16,16-dimethyl analogs are prepared by aerobic incubation of all-cis16-methyl-8,11,14-eicosatrienoic acid or all-cis16,l6-dimethyl-8,11,14-eicosatrienoic acid with comminuted sheepvesicular gland tissue or with the enzyme system contained therein, in asubstantially aqueous medium. Likewise, following the procedures of saidissued patent, the optically active 16- ethyl, 16,16-diethyl, and16-ethyl-16-methyl analogs are also prepared. For additional proceduraldetails, see also U.S. Pat. No. 3,296,091, Kupiecki, Life Sciences, 4,1811 (1965), Struijk, Rec. Trav. Chim. 85, 1233 (1966), and Nugteren etal., Rec. Trav. Chim., 85, 405 (1966).

These biological oxidations produce mixtures of the PGE and PGF forms ofthe 16-methyl analogs. Likewise, there are produced mixtures of the PGE,and PGF forms of the 16,16-dimethyl, of the 16-ethyl, of the16,16-diethyl, and of the 16-ethyl-l6-methyl analogs, respectively. Thecomponents of each of these mixtures are separated and each component ispurified as set forth in U.S. Pat. No. 3,296,091, or by other proceduresknown to be useful for separating mixtures of the known prostaglandinsand purifying the individual components. In particular, advantage istaken of the greater polarity of the PGF a -type compound in comparisonwith the PGE,-type compound in these separations, using chromatographyon acid-washed silica gel, reversed-phase partition chromatography,preparative thin-layer chromatography, or countercurrent distribution,or a combination or those.

The invention can be more fully understood by the following examples andpreparations:

All temperatures are in degrees centrigrade.

Brine are used herein refers to aqueous saturated sodium chloridesolution.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Racemic 16-Methyl-PGEMethyl Ester (Formula VII: D is There is next prepared the Formula-IXcompound. To a stirred solution of the Formula-VIII olefin above (10.0g.) and methyl 7-iodoheptanoate (12 g.) in 250 ml. of tetrahydrofuranunder nitrogen at 25 C. is added dropwise a solution of potassiumtert-butoxide (7.0 g.) in 500 ml. of nitrogen-purged tetrahydrofuran,over a period of 45 min. The resulting mixture is acidified at once withabout 120 ml. of hydrochloric acid, and then concentrated under reducedpressure below 40 C. Water (400 ml.) is added to the residue, and themixture is extracted with successive 400-ml. portions of diethyl ether.The ether extract is washed with water, then with brine, dried oversodium sulfate, and then evaporated to leave a residue containing theFormula-1X compound, viz. methyl 7-[endo-6-(3- methyl- 1 -heptenyl)-3-oxobicyclo[3. 1 .0]hex-2 ayl]heptanoate, as a mixture of two pairs ofracemates.

There is next prepared the Formula-X glycol. A solution of the FormulaIX racemates above g.) in 160 ml. of tetrahydrofuran is stirred at 50 C.under nitrogen and osmium tetroxide (1.0 g.) is added followed by asolution of potassium chlorate (6.5 g) in 75 ml. of water. Stirring iscontinued at 50 C. for 3 hrs.; then the tetrahydrofuran is removed byevaporation under reduced pressure and the residue is extracted withmethylene chloride. The organic layer is washed with water, dried oversodium sulfate, and evaporated to give a mixture of Formula-X glycols.This mixture of glycols is chromatographed over 2 kg. of silica gelwet-packed with ethyl acetate in Skellysolve B, eluting successivelywith 15, 25, 35, 60, and 80% ethyl acetate in Skellysolve B (isomerichexanes). Those fractions of eluate shown by TLC (thin layerchromatography) to contain the desired glycols are combined and thenevaporated to give the Formula-X product wherein R is hydrogen and R ismethyl, as a mixture of isomeric glycols.

The above glycol mixture (7.1 g.) is dissolved in 90 ml. of pyridine andstirred at 0 C. under nitrogen while 8.5 ml. of methanesulfonyl chlorideis added over a period of 15 min. The mixture is stirred at 0 C. for 2.5hrs., then cooled to -15 C. and 10 ml. of ice and water is added slowly.After 5 min. additional stirring at 5 to 0 C. the mixture is poured into500 ml.'of ice and water. Cold 1:3 dichloromethane-ether (200 m1.) isadded, followed by 360 ml. of cold 3M. hydrochloric acid, and themixture is extracted rapidly with methylene chloride-ether. The organicextracts are washed with 2% sulfuric acid, water, aqueous bicarbonate,and brine, then dried over sodium sulfate and evaporated to give theFormula-X1 bismethanesulfonate.

The above bismesylate of the mixed glycols (10.5 g.) is dissolved in 400ml. of 2:1 acetone-water and allowed to stand about 18 hrs. at 25 C.,then is diluted with 400 ml. of water and the acetone is removed byevaporation under reduced pressure. The aqueous residue is extractedwith ethyl acetate and the extracts are washed with aqueous sodiumbicarbonate and brine, then dried over sodium sulfate and evaporated togive a mixture of isomeric Formula-X11 products. The residue containsfour racemates, i.e. four pairs of isomeric Formula-X11 products havingdifferent asymmetric centers at C-8, C-15 and C-l6. The following procedures are directed toward the separation of the racemates. Two of theseracemates are similar in being more polar than the other two racemates,and are separated from the other two by means of silica gelchromatography.

The residue is chromatographed over 1.6 kg. of silica gel wet-packedwith 30% ethyl acetate in Skellysolve B, eluting with 8 l. of 30%, 4 l.of 40%, 13 l. of 60%, and 16 l. of ethyl acetate in Skellysolve B, 10 l.of ethyl acetate, then gradient elution with 5 l. of ethyl acetate, and5 l. of 5% methanol in ethyl acetate, collecting 500 ml. fractions.Those fractions shown by TLC to contain the two more polar (slowereluting) racemates are combined and concentrated.

These mixed racemates have the natural prostaglandin configuration atC-8 and C-15, viz. R and S respectively, and differ in theirstereochemistry at C 16. To separate then, the Formula-XII product istransformed to the bis(trimethylsilyl)ether. A solution of theFormula-XII product (5.0 g.), hexamethyldisilazane (25 ml.), andtrimethylchlorosilane (IO-ml.) in 20 ml. of tetrahydrofuran is leftstanding at about 25 C. for 20 hours. The mixture is filtered through abed of diatomaceous earth and the filtrate is concentrated byevaporation under reduced pressure.

The residue is chromatographed over 1.6 kg. of silica gel wet-packedwith 30% ethyl acetate in Skellysolve B, eluting with 8 l. of 30%, 4 l.of 40%, 13 l. of 60%, and 16 l. of 80% ethyl acetate in Skellysolve B,10 l. of ethyl acetate, then gradient elution with 5 l. of ethylacetate, and 5 l. of 5% methanol in ethyl acetate, collecting 500 ml.fractions.

Those fractions shown by TLC to contain the separated silylatedracemates, free of intermediates and by-products, are combined andconcentrated. The trimethylsilyl groups are replaced with hydrogen bycontacting each residue with a solution of 50 ml. of methanol and 20 ml.of water at 25 C. for 16 hrs., thereafter removing solvents underreduced pressure to yield the racemic Formula-XII title compounds. Thoseracemates shown to have more biological activity in smooth muscle striptests (see J. R. Weeks et al, Journal of Applied Physiology 25, (No. 6),783 (1968)) are more useful for the above-described purposes.

Following the procedures of Example 1, but replacing the Formula-VIIIcompound of that example with the Formula-VIII compound wherein R ishydrogen and R is ethyl, there are obtained the corresponding racemic16-ethyl-PGE products.

Following the procedures of Example 1, but replacing the Formula-V111compound of that example with the Formula-VIII compound wherein R and Rare both methyl, there is obtained the corresponding 16,16-dimethyl-PGEracemic product. For these di- 16-substituted compounds the final stepabove, utilizing chromatography of the silylated product, may be omittedbecause of the absence of an asymmetric center at C-16.

Likewise replacing the Formula-Vlll compound of Example 1 with theFormula-VIII compounds wherein R and R are ethyl, and wherein R is ethyland R is methyl, there are obtained the corresponding 16,16- diethyland16-ethyl-l6-methyl-PGE compounds, respectively.

Following the procedures of Example 1 but employing Formula-IX compoundswherein R is alkyl of 2 to 8 carbon atoms, inclusive, instead of methyl,there are obtained the corresponding PGE -type compounds wherein R isalkyl of 2 to 8 carbon atoms.

EXAMPLE 2 (Formula XX, Chart C: G is -(CH CH haloethyl is 5 CH CCl R ishydrogen; R is methyl; and is endo).

Refer to Chart C. The Formula-XV compound, i.e. the Formula-[X compoundof Example 1 as the methyl ester, is reduced with sodium borohydride tothe Formula-XVI compound as follows. To a solution of the Formula-XVcompound (4.0 g.) in l 10 ml. of absolute ethanol at C. is added asolution of sodium borohydride (1.5 g.) in 10 ml. of water, withstirring. After stirring for 2.5 hrs. at 05 C., about 40 ml. of acetoneis added, and, after min., the mixture is evaporated under reducedpressure. The residue is extracted with dichloromethane, and the extractis washed successively with dilute hydrochloric acid and brine, dried,and evaporated to give the Formula-XVI compound.

This ester is dissolved in a mixture of methanol (100 ml.) and 45%aqueous potassium hydroxide solution (30 ml.), and the solution isstirred under nitrogen at 25 C. for 15 hrs. Two volumes of water arethen added, and the mixture is acidified with cold hydrochloric acid andthen extracted with a mixture of dichloromethane and diethyl ether(1:3). The extract is washed with brine, dried, and evaporated to givethe Formula-XVII hydroxy acid.

Jones reagent (7 ml. of a solution of 21 g. of chromic anhydride, 60 ml.of water, and 17 g. of concentrated sulfuric acid) precooled to 0 C., isadded dropwise to a solution of this hydroxy acid in 120 ml. of acetoneat 0 C. The mixture is stirred 5 min. at 0 C. Then, 5 volumes of waterare added, and the mixture is extracted with a mixture ofdichloromethane and diethyl ether (1:3). The extract is washedsuccessively with dilute hydrochloric acid and brine, dried, andevaporated to give the Formula-XIX 3-oxo compound.

To a solution of the above Formula-XIX free acid (2.0 g.) in 100 ml. ofdichloromethane are added, successively, B,,B,B-trichloroethanol (25ml.), pyridine (15 ml.), and dicyclohexylcarbodiimide (4.0 g.). Thismixture is stirred 3 hrs. under nitrogen at 25 C. Water (50 ml.) is thenadded, and the mixture is stirred min. The dichloromethane is evaporatedunder reduced pressure, and the residue is extracted repeatedly withethyl acetate. The combined extracts are washed with ice-cold 3 Nhydrochloric acid. Then, the extracts are washed successively withaqueous sodium bicarbonate solution and brine, dried, and evaporatedunder reduced pressure. The residue is chromatographed on 600 g. ofsilica gel, eluting with 101. ofa 20l00% ethyl acetate-Skellysolve Bgradient, collecting 250-ml. fractions. The fractions shown by TLC tocontain the desired product free of starting materials and by-productsare combined and evaporated under reduced pressure to yield theFormula-XX title compound, i.e., the trichloroethyl ester.

Following the procedure of Example 2, but using in place of theFormula-XV 3-oxobicyclo[3.l.O]hexane ester, each of the endo and exoFormula-IX intermediates after Example 1, there are obtained thecorresponding B,,B,B-trichloroethyl esters of those 3-oxobicyclo[3.l.0]hexane acids. Thus, instead of the 3-methyl Formula-XXheptanoates, there are obtained the 3,3-dimethyl, 3-ethyl, 3,3-diethyl,and 3-ethyl-3- 28 methyl Formula-XX heptanoates as trichloroethylesters.

EXAMPLE 3 Racemic 16-Methyl-PGE (Formula VII: D is I I w 1.

R and R are hydrogen; and R is methyl). 1 5 Refer to Chart B. Followingthe procedures of Example l but replacing the Formula-IX methyl estercompound used therein with the Formula-XX trichloroethyl ester compoundof Example 2, there is obtained the corresponding racemic l6-methyl-PGEtrichloro- 20 ethyl ester.

Zinc dust (420 mg.) is added to a solution of this B,B,,B-trichloroethylester (100 mg.) in 5 ml. of a mixture of acetic acid and water (9:1v/v). This mixture is stirred under nitrogen 2 hrs. at 25 C. Ethylacetate (4 volumes) is then added, followed by addition of one N.hydrochloric acid (1 volume). The ethyl acetate layer is separated,washed with water and then with brine, dried, and evaporated. Theresidue is chromatographed on g. of acid-washed silica gel (SilicarCC4), and eluted with 100 ml. of 50%, 100 ml. of 80%, and 200 ml. of100% ethyl acetate in Skellysolve B, collecting -ml. fractions. Thefractions containing l6-methyl- PGE, and no starting material ordehydration products as shown by TLC are combined and evaporated to givethe Formula-VII title compound.

Following the procedures of Examples 3 and 1, each of the haloethylester Formula-XX intermediates of Example 2 are transformed to thecorresponding racemic haloethyl ester PGE -type compound and thence tothe corresponding racemic free acid. There is thus obtained racemic16,16-dimethyl-PGE l6-ethyl-PGE- l6,16-diethyl-PGE and16-ethyl-l6-methyl-PGE EXAMPLE 4 Racemic l6-Methyl-PGF and l6-Methyl-PGF(Formula VII: D is R and R are hydrogen; R is methyl, and is alpha orbeta).

Refer to Chart A. A solution of racemic l6-methyl- PGE, methyl ester(Example 1, 400 mg.) in 20 ml. of isopropyl alcohol is cooled to 0 C.under nitrogen and a solution of sodium borohydride (0.2 g.) in 4 ml. of60 cold water is added. The mixture is stirred at 0 C. for 2.5 hrs.,then 1 ml. of acetone is added and, 10 min. later, 1.2 ml. of glacialacetic acid. The organic solvents are removed by evaporation underreduced pressure and the residue is mixed with water and ethyl acetate.The organic extracts are washed with water and brine, dried over sodiumsulfate, and concentrated to give a mixture of racemic l6-methyl-PGFmethyl ester and racemic l6-methyl-PGF methyl ester. This mixture ischromatographed on 150 g. of silica gel wet-packed with 30% ethylacetate in cyclohexane, eluting with 500 ml. of 30%, 500 ml. of 50%, 500ml. of 60%, 500 ml. of 70%, 1.5 l. of 80% and L 1. of 90% ethyl acetatein cyclohexane, l. of ethyl acetate, 1 l. of 5% and l l. of methanol inethyl acetate, taking 50 ml. eluate fractions. Those fractions shown byTLC to contain the desired products free of starting material andby-products are combined, then concentrated to give the Formula-VII PGFand PGF pounds, respectively, as their methyl esters.

A solution of racemic l6-methyl-PGF methyl ester (0.15 g.) in a mixtureof 4.5 ml. of methanol and 1.5 ml. of water is cooled to 5 C., and 0.6ml. of 45% aqueous potassium hydroxide is added. The mixture is leftstanding 3.5 hrs. at C., then is diluted with 75 ml. of water andextracted once with ethyl acetate to remove any neutral material. Theaqueous layer is separated, made acid with dilute hydrochloric acid andextracted 4 times with ethyl acetate. The extracts are combined andwashed 3 times with water, once with brine, dried over sodium sulfate,and evaporated to give racemic l6-methyl-PGF Likewise, racemicl6-methyl-PGF methyl ester is saponified with aqueous potassiumhydroxide and acidified to yield the free acid of racemic l6-methyl-PGFFollowing the procedures of Example 4, each of the PGE -type compoundsdescribed in the paragraphs following Example I are transformed to thecorresponding PGF and PGF p -type esters and free acids, e.g.16,16-dimethyl-PGE ether ester yields 16,16-dimethyl-PGF and -PGF ethylesters and free acids.

EXAMPLE 5 Racemic l6-Methyl-PGA Ethyl Ester and Free Acid (Formula VII:D is R is ethyl or hydrogen; R is hydrogen; and R is methyl) I Refer toChart A.

I. Using hydrochloric acid. A solution of racemic l6-methyl-PGE ethylester (400 mg.) in a mixture of tetrahydrofuran (5 ml.) and 0.5 Nhydrochloric acid (5 ml.) is maintained under nitrogen at 25 C. for 5days. The resulting mixture is diluted with one volume of brine andextracted with a mixture of diethyl ether and dichloromethane (3:l). Theextract is washed with brine, dried, and evaporated. The residue (380mg.) is dissolved in diethyl ether, and the solution is extracted withcold 5% aqueous sodium bicarbonate solution to give an aqueous layer Aand a diethyl ether layer B. Aqueous layer A is acidified with dilutehydrochloric acid and then extracted with dichloromethane. This extractis washed with brine, dried, and evaporated to give the title compoundfree acid. Diethyl ether layer B is evaporated to give the titlecompound ethyl ester.

ll. Using acetic acid. A solution of racemic l6-methyl-PGE ethyl esterin a mixture of a glacial acetic acid (9 ml.) and water (1 ml.) isheated under nitrogen at 60 C. for l8 hrs. Then, the acetic acid andwater are -type com- 1 evaporated under reduced pressure, and theresidue is chromatographed on 500 g. of acid-washed silica gel, elutingwith a 25l00% gradient of ethyl acetate in Skellysolve B. The fractionscontaining the desired product free of starting material and by-productsas shown by TLC are combined and evaporated to give the title compoundethyl ester.

Following the procedure of Example 5, each of the racemic PGE -typecompounds described in the paragraphs following Example I aretransformed to the corresponding PGA -type esters and free acids, e.g.l6,l6-dimethyl-PGE methyl ester yields 16,16- dimethyl-PGA, methylester.

Likewise following the procedure of Example 5, each of the haloethylester PGE -type compounds of and following Example 3 is transformed tothe corresponding haloethyl ester PGA -type compound. Thereafter,following the procedure of Example 3, each of the haloethyl ester PGA-type compounds is transformed with zinc, acetic acid, and water to thecorresponding racemic free acid PGA -type compound. There is thusobtained racemic 16,16-dimethyl-PGA l6-ethyl- PGA l6,l6-diethyl-PGA andl6-ethyl-l6-methyl- PGA EXAMPLE 6 Racemic l6-methyl-PGA Methyl Ester.

Refer to Chart B. A solution of the Formula-XI bismesylate of Example 1(about 10 g.) in ml. of acetone is mixed with 10 ml. of water and 20 ml.of saturated aqueous sodium bicarbonate solution. The mixture is heatedat reflux under nitrogen for 4 hrs. Then, the mixture is cooled,acidified with 5% hydrochloric acid, and extracted with ethyl acetate.The extract is washed with brine, dried, and evaporated to give thetitle compound.

Following the procedure of Example 6, each of the bismesylates obtainedafter Examples 1 and 3 is transformed to the corresponding PGA-typeester, including the Bfifi-trichloroethyl esters. There are used forpreparing the PGA-type free acids following the procedure of Example 3.

EXAMPLE 7 Racemic l6-Methyl-PGB (Formula VII: D is R and R are hydrogen;and R is methyl).

The procedure shown in Chart A is followed. A solution of racemicl6-rnethyl-PGE (Example I, 200 mg.) in ml. of 50% aqueous ethanolcontaining 10 g. of potassium hydroxide is kept at 25 C. for 10 hrs.under nitrogen. Then, the solution is cooled to 10 C. and neutralized byaddition of 3 N. hydrochloric acid at 10 C. The resulting solution isextracted repeatedly with ethyl acetate, and the combined ethyl acetateextracts are washed with water and then with brine, dried, andevaporated to give the title compound.

Following the procedure of Example 7, 16,16- dimethyl-F'GE and -PGA areeach transformed to 16,16-dimethyl-PGB,.

31 Following the procedure of Example 7, the Formula- VII PGE -type andPGA -type compounds described above are transformed to the correspondingPGB compounds.

EXAMPLE 8 l6-Methyl-PGB Methyl Ester.

A solution of diazomethane (about 0.5 g.) in diethyl ether (25 ml.) isadded to a solution of 16-methyl-PGB (50 mg.) in 25 ml. of a mixture ofmethanol and diethyl ether (1:1). The mixture is allowed to stand at 25C. for min. Then, the mixture is evaporated to give the title compound.

Following the procedure of Example 8, each of the other specific PGB-type, PGA -type, PGE -type, and PGF -type free acids defined above isconverted to the corresponding methyl ester.

Also following the procedure of Example 8, but using in place of thediazomethane, dizaoethane, diazobutane, l-diazo-2-ethylhexane, anddiazocyclohexane, there are obtained the corresponding ethyl, butyl, 2-ethylhexyl, and cyclohexyl esters of l6-methylPGB. In the same manner,each of the other specific PGB -type, PGA -type, PGE -type, and PGF-type free acids defined above is converted to the corresponding ethyl,butyl, 2-ethylhexyl, and cyclohexyl esters.

EXAMPLE 9 16-Methyl-PGE Sodium Salt.

A solution of 16-methyl-PGE (100 mg.) in 50 ml. of a water-ethanolmixture (1:1) is cooled to 5 C. and neutralized with an equivalentamount of 0.1 N aqueous sodium hydroxide solution. The neutral solutionis evaporated to give the title compound.

Following the procedure of Example 9 but using potassium hydroxide,calcium hydroxide, tetramethylammonium hydroxide, andbenzyltrimethylammonium hydroxide in place of sodium hydroxide, thereare obtained the corresponding salts of l6-methyl-PGE Also following theprocedure of Example 9 each of the PGE -type, PGF -type, PGA -type, andPGB -type acids defined above is transformed to the sodium, potassium,calcium, tetramethylammonium, and benzyltrimethylammonium salts.

The various examples given above describe the preparation of racemicintermediates and final products. Each of the intermediates and finalproducts named and defined above is also obtained in each of theenantiomeric forms, (1 and l, by resolution of that compound or byresolution of an intermediate used to prepare that compound. Forexample, optically active 16-methyl- PGA free acid is prepared byresolution of racemic 16-methyl-PGA free acid (Example 5) or bydehydration as in Example 5 of optically active 16-methyl- PGE free acidwith the same absolute configuration. These resolutions are carried outby procedures known in the art, and may be used to obtainprostaglandin-like materials having the stereochemical configuration ofthe natural prostaglandins, other than at C-16, as typified by thefollowing example.

EXAMPLE 1O l6-Methyl-PGE Methyl Ester Compounds having the NaturalConfiguration of PGE except at C-16.

Refer to Chart B. There is first prepared bicyclic olefin VIII followingthe procedures of Example 1 but employing(2-methylhexyl)triphenylphosphonium bromide obtained fromd-l-bromo-2-methy1hexane. That d-isomer is obtained by methods known inthe art, e.g. by resolving d-Z-methylhexanoic acid (see P. A. Levene andL. W. Bass, Journal of Biological Chemistry 70, 211 (1926)), reducingthat acid to the corresponding primary alcohol with lithium aluminumhydride, and converting that alcohol to the halide by reacting it withPBr HBr, or any of the other halogenating agents known in the art to beuseful for this purpose.

Next, the Formula-IX bicyclic intermediate is prepared, wherein R ishydrogen; R and R are methyl; G is (CH -CH and is endo, following theprocedures of Example 1. The l6-methyl Formula-IX compound is obtainedas a mixture of diastereomers which are separated as follows. Themixture is chromatographed on a silica gel column (500 g) wet-packedwith 5% ethyl acetate-Skellysolve B (one liter) and eluted with a 5 to25% ethyl acetate gradient in Skellysolve B. Those fractions shown byTLC to contain the respective Formula-IX compounds are combined andevaporated to give the separate SR and 8S Formula-1X compounds in whichthe stereochemistry at C-l6 is the same as that of the d-isomerintermediate above.

Thereafter, following the procedures of Example 1, each of the aboveFormula-IX compounds is transformed to the Formula-X mixed glycols,thence to the Formula-XI bismesylates, and finally to a mixture of theFormula-XII 16-methyl-PGE compound and the corresponding Formula-XII15-epil 6-methyl-PGE compound. Each mixture of PGE -type and 15-epi- PGE-type compounds is separated into the respective components bychromatography on a silica gel column (500 g.) wet-packed with 50% ethylacetate-Skellysolve B (1 liter), and eluted with 50% ethyl acetate-Skellysolve B, then ethyl acetate, and finally 10% ethanolethyl acetate.Those more polar and less polar fractions shown by TLC to contain thePGE -type and IS-epi-PGE -type compounds, respectively, are combinedseparately and concentrated to yield the respective compounds.

Likewise following the above procedures, there is employed the(Z-methylhexyl)triphenylphosphonium bromide obtained froml-l-bromo-2-methylhexane. That l-isomer is obtained by methods known inthe art from resolved l-2-methylhexanoic acid (See P. A. Levene and L.A. Mikeska, Journal of Biological Chemistry 84, 571 (1929)). There arefinally obtained the respective optically active PGE -type and15-epi-PGE type compounds having a different configuration at C-16 thanthose obtained from the d-isomer intermediate above.

Of the above separated PGE -type compounds, those which are shown bysmooth-muscle strip tests to have more biological response are the moreuseful compounds for the above-described purposes.

Following the procedures of Examples 10 and 3, and following Example 3,there are obtained the optically active 16-methyl-PGE free acidcompounds.

Following the procedures following Example 5, the optically activel-methyl-PGE, compounds are transformed to the optically activel6-methyl'PGA compounds.

Following the procedures of Example 4, the optically activel6-methyl-PGE compounds are transformed to the optically activel6-methylPGF and -PGF compounds.

Following the procedures of Example 7, the optically active16-methyl-PGE compounds are transformed to the optically activel6-methyl-PGB compounds.

Following the procedures of Example and of the above paragraphsfollowing Example 10, but employing the l6-ethyl Formula-IX compoundsinstead of the l6-methyl Formula-IX compounds, there are obtained thecorresponding optically active l6-ethyl-PGE -PGF -PGF -PGA and -PGBcompounds.

EXAMPLE 1 1 Natural-Configuration l6,l6-Dimethyl-PGE Methyl Ester.

Refer to Chart B. The Formula-IX bicyclic intermediate wherein R R and Rare methyl; G is (Cl-l CI-l and is endo is prepared following theprocedures of Example 1.

The Formula-IX compound is then resolved as its optical isomers by themethod of Corey et al., J. Am. Chem. Soc. 84, 2938 (1962), by reactingthis keto compound with optically active L(+)-2,3-butanedithiol in thepresence of p-toluenesulfonic acid. The diastereomeric ketals areseparated on a preparative chromatographic column, and are thenhydrolyzed separately to the Formula-1X bicyclic ketone, by methodsknown in the art, e.g. using 1:1 hydrochloric acid-water intetrahydrofuran at 25 C. for 6 hrs. Thereafter, following the procedureof Example 1, each of the isomeric FormulalX compounds is transformed tothe corresponding Formula-XII compounds. The PGE title compounds andl5-epi-PGE compounds are separated following the procedures of Example1, using silica gel chromatography. Because of the absence of asymmetryat C-l6, the silylation step and subsequent chromatography are omittedfor the l6,l6-dimethyl compounds.

The optically active l6,l6-dimethyl-PGE -type free acids are preparedfollowing the procedures of Example 3, utilizing the haloethyl esterprepared from the separated Formula-IX compound above by the proceduresof Example 2.

Following the procedures of Example 1 1, and of the above paragraph, butemploying the appropriate l6,l6- dialkyl Formula-IX compound asdisclosed herein, there is obtained the corresponding optically activel6,l6-dialkyl PGE type compound, including the esters and free acidswithin the scope of R as defined above.

Following the procedures outlined in Chart A and as set forth inExamples 4, 5, 6, and 7, the optically active 16,16-dialkyl-PGEcompounds disclosed herein are transformed to the correspondingoptically active l6,l 6-dialkyl-PGF PGF 3 PGA and PGB type compounds,respectively. Thus, there are obtained optically activel6,l6-dimethyl-PGE -PGF -PGF, -PGA and PGB,; 16,16-diethyl-PGE -PGF,p-PGA and -PGB and l6-ethyl-l6-methyl POE -PGF; -PGF p -PGA and -PGBThere is obtained l6,l6-dimethyl-PGE mass spectral peaks (fortrimethylsilyl derivative) at 583, 499, and 409.

EXAMPLE l2 l6,l6-dimethyl PGF methyl ester A solution of diazomethane(about 0.5 g.) in 25 ml. of diethyl ester is added to a solution of16,16-dimethyl PGF in about 25 ml. of a mixture of methanol and diethylether (1:1). After the mixture has stood at about 25 C. for about 5min., it is concentrated under reduced pressure to yield l6,l6-dimethylPGF methyl ester, having infrared spectral absorptions at 3380, 1740,1460, 1435, 1360, 1255, 1195, 1172, 1110, 1075, 1015, 995 and 970 cm.

Following the procedure of Example 12, each of the other compounds offormula VII, wherein R is hydrogen are likewise converted to thecorresponding methyl ester.

In the same manner other alkyl esters of formula VII are likewiseprepared from the corresponding free alcohols by substituting theselected diazoalkane in place of diazomethane.

We claim:

1. An optically active compound of the formula or a racemic compound ofthat formula and the mirror image thereof, wherein indicates alpha orbeta attachment of hydroxyl to the cyclopentane ring, R is hydrogen,alkyl of one to 8 carbon atoms, inclusive, or a pharmacologicallyacceptable cation, and wherein R and R are methyl.

2. An optically active compound according to claim 1.

3. A racemic compound according to claim 1.

4. Racemic l6-methyl-PGF 5. 16,16-Dimethyl-PGF an optically activecompound according to claim 1 wherein R is hydrogen and is alpha.

6. Racemic l6,l6-dimethyl-PGF a compound according to claim 1 wherein Ris hydrogen and is alpha.

7. 16,1 6-Dimethyl-PGF an optically active compound according to claim 1wherein R, is hydrogen and is beta.

8. Racemic l6,l6-dimethyl-PGF a compound according to claim 1 wherein Ris hydrogen and is beta.

9. l6,l6-Dimethyl-PGF methyl ester, an optically active compoundaccording to claim 1 wherein R is methyl and is alpha.

l0. Racemic l6,l6-dimethyl-PGF methyl ester, a compound according toclaim 1 wherein R is methyl and is alpha.

. Column 30, line-l3, "ls6,l6-d1'methyl-.PGA, methyl ester shoul UNITEDSTATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO.3

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line 17, "of" should read or Column 3, line 10, "PFG a" shouldread PGF a Column 4, line 37, "PFG" should read PGFor Column 9; line 65,"liquids" should read liquid Column ll, line 12, "PGF B, and P68 shouldread PGF B, PGA and PGB Column 22, line 62, "treatment of the sale"should read treatment of the salt Column 23, line 2, "separated and lforms" should read separate d and l forms Column 23, line 20, "-PGF -or"should read PGFw Column 23, line 2l, '-'l6-ethyl-PGE ethyl-PGE and l andPGHa'? should read l6-ethyl-PGE sand PGF-w,

Column 24, line *2, r"-PGF should read -PG|E d read l6,l6-

dimethylPGA methyl ester Column 3l line 23, "l6-methyl-PGB." should readl6-methyl-PGB Column 33, line 58, "-PGF a, PGF-m', should read PGHu,-PGF1B Column 33, line 59, PGE -PGF B, should read PGE PGFw, 'PGFqB,

Signed and Scaled this Fifth Day of Mayl98l [SEAL] Anm:

ru-zNe o. TEGTMEYER Arresting Qfl'rctr Acting Commissioner of Patent:and Trademarks

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. An optically activecompound according to claim
 1. 3. A racemic compound according toclaim
 1. 4. Racemic 16-methyl-PGF1 .
 5. 16,16-Dimethyl-PGF1 , anoptically active compound according to claim 1 wherein R1 is hydrogenand * is alpha.
 6. Racemic 16,16-dimethyl-PGF1 , a compound according toclaim 1 wherein R1 is hydrogen and * is alpha.
 7. 16,16-Dimethyl-PGF1 ,an optically active compound according to claim 1 wherein R1 is hydrogenand * is beta.
 8. Racemic 16,16-dimethyl-PGF1 , a compound according toclaim 1 wherein R1 is hydrogen and * is beta.
 9. 16,16-Dimethyl-PGF1 ,methyl ester, an optically active compound according to claim 1 whereinR1 is methyl and * is alpha.
 10. Racemic 16,16-dimethyl-PGF1 , methylester, a compound according to claim 1 wherein R1 is methyl and * isalpha.